In percutaneous transluminal coronary angioplasty (PTCA), a balloon catheter is inserted through a brachial or femoral artery, positioned across a coronary artery occlusion, and inflated to compress against atherosclerotic plaque to open, by remodeling, the lumen of the coronary artery. The balloon is then deflated and withdrawn. Problems with PTCA include formation of intimal flaps or torn arterial linings, both of which can create another occlusion in the lumen of the coronary artery. Moreover, thrombosis and restenosis may occur several months after the procedure and create a need for additional angioplasty or a surgical by-pass operation. To address these issues, stents, which are small, intricate, implantable medical devices, play an important role in PTCA. Stents are generally implanted to reduce occlusions, inhibit thrombosis and restenosis, and maintain patency within vascular lumens such as, for example, the lumen of a coronary artery.
Stents are often modified to provide drug delivery capabilities to further address thrombosis and restenosis. Stents are being coated with a polymeric carrier impregnated with a drug or therapeutic substance. A conventional method of coating includes applying a composition including a solvent, a polymer dissolved in the solvent, and a therapeutic substance dispersed in the blend to the stent by immersing the stent in the composition or by spraying the composition onto the stent. The solvent is allowed to evaporate, leaving on the stent strut surfaces a coating of the polymer and the therapeutic substance impregnated in the polymer. However, dipping and spraying techniques requires for large amounts of drugs and solvents to be used which can be hazardous for the operator and the environment.
An additional new venue for intravascular therapy is the drug coated balloon. These devices are dilatation balloons equipped with a drug containing coating. This coating consists of a therapeutic drug(s) combined with a polymeric carrier or excipient which may be released into the bloodstream. During peripheral angioplasty, commonly known as percutaneous transluminal angioplasty (PTA), a balloon dilation is performed, to dilate an occlusive lesion, with the drug present on the outer coating layer of the balloon. PTA is most commonly used to treat narrowing of the leg arteries, especially, the iliac, external iliac, superficial femoral and popliteal arteries. PTA can also treat narrowing of veins, and other blood vessels. The drug containing outer coating is then transferred to the inner wall of the blood vessel. The function of the transferred drug coating is to reduce restenosis, or other undesirable sequelae of the procedure. Drug coated balloons with paclitaxel are presently approved for use in treatment of the coronary arteries. However, drug coated balloons are being heavily considered for use in the peripheral vasculature as shown by the results of the THUNDER and FemPac clinical trials. (Tepe G, et al. N Eng J Med, 358; 7, 2008, p 689; Werk M, et al. Circ. 2008; 118: 1358-1365.)
Furthermore, in a study which evaluated restenosis and the rate of major adverse cardiac events (MACE) such as heart attack, bypass, repeat stenosis, or death in patients treated with drug eluting balloons and drug eluting stents, the patients treated with drug eluting balloons experienced only 3.7 percent restenosis and 4.8 percent MACE as compared to patients treated with drug eluting stents, in which restenosis was 20.8 percent and 22.0 percent MACE rate. (PEPCAD I/II, M. Unverdorben, TCT, October 2007).
One of the putative advantages of PTA balloons is the minimization of restenosis after stent implantation. In some PTCA cases, it was found that within about six months of stenting, a re-narrowing of the blood vessel characterized by a growth of smooth muscle cells often persisted. Restenosis was discovered to be a “controlled injury” of the angioplasty procedure and was analogous to a scar forming over an injury. Drug eluting stents (DES) is one of the solutions to address restenosis by the use of anti-proliferative and/or cytostatic drugs to interfere with the vessel cell growth and migration processes.
There are several current theories about the mechanism by which a drug coated balloon transfers drug to the vessel wall. One theory, for example, is that upon balloon expansion, drug mechanically fractures or dissolves from the coating, diffuses to the vessel wall and then permeates into the vessel wall. A second theory is that upon balloon expansion the balloon coating is transferred to the vessel wall, and then drug permeates into the vessel wall from the coating adhered to the vessel wall. Another theory is that the balloon expansion creates tears and microfissures in the vessel wall and a portion of the coating inserts into the tears and microfissures. Drug then permeates into the vessel wall from the coating within the tears and fissures. Yet another theory is that upon balloon expansion, a layer of dissolved drug and coating excipients is formed at a high concentration on the vessel wall as a boundary layer. Thus it would be advantageous to have a consistent uniform coating applied to the balloon surface. One that is formulated to exhibit one of the above properties.
The current dipping and spray techniques are very wasteful methods of coating medical devices, most particularly when very small geometrical structures like stents are being coated. For example, during the spray application of the drug composition, a majority of the coating material, including a drug, is wasted as only a fraction of the spray flux is intercepted by the stent struts. Considering that the pharmaceutical agents are costly, it would be beneficial to reduce coating process waste.
Moreover, dipping and spray coating processes can tend to promote a great deal of coating defects. Coating defects can include an uneven thickness in stent and balloon coating, which would in effect translate into uneven distribution of the drug across the surface body of the medical device. Stent coating defects can also include “webbing” between stent struts (over the gaps or opening between the struts) or coating “pools” which are excessive gatherings on the stent struts. Webbing and pooling can lead to adverse biological responses when the stent is implanted. A coating process which reduces or eliminates coating defects and is more superior than the conventional coating processes would be very desirable.
Finally, dipping and spray coating processes can lead to manufacturing inconsistencies between batches of stents and balloons during production. Lack of control in the coating process can lead to, for example, an unpredictable drug distribution and inconsistent coating topography between different batches of stents or balloons. An unpredictable drug distribution means that some stents can have more drug than was intended to be deposited and some can have significantly less. When coating balloons, a uniform coating is desired in order to treat the vessel uniformly. The possibility of treating the lesion in a more uniform manner is one potential advantage for a drug coated balloon versus a stent. Furthermore, drug transfer from the balloon to the vascular wall tissue and occurs within one minute, and preferably within 30 seconds upon inflation of the balloon. Therefore, a need exists for consistent and uniform drug coating to facilitate efficient drug transfer to all areas of the vessel wall that is in contact with the balloon surface. A large discrepancy in what was intended to be deposited is definitely unwanted since it will not be known with accuracy how much drug a patient will receive. Inconsistent coating topography means that the release rate of the drug from stent-to-stent can vary. Again, it is obviously more desirable to be able to accurately provide, with a very small differential in the mean deviation, the average release rate of the drug from the stent or balloon being manufactured.
All manufacturers have invested a great amount of research in improving their coating techniques. One proposed method has been by electrostatic deposition, such as that disclosed in U.S. application Ser. No. 11/093,166, to Cameron K. Kerrigan, which is incorporated herein by reference. Electrostatic coating techniques are well known in the art. Particles of a drug are charged. The stent is grounded or is oppositely charged. The electrostatic attraction between the stent and drug results in a more efficient drug deposition, with less waste and more consistent coating characteristics. This is particularly beneficial for stents which have a very complex, three dimensional tubular structure, with struts separated from each other by gaps. Dilatation balloons, particularly for the peripheral vessels, can be quite large, up to 8×100 mm in size. Coating these large medical devices can consume large quantities of drug making an efficient coating process highly desirable.
Stents that are made from metallic materials provide for conductive surfaces which can be easily charged for electrostatic deposition. However, stents that have been pre-coated with a polymer, for example a polymer primer without a drug, or those that are made from a polymer provide for electrically non-conductive surfaces and cannot be grounded, biased or polarized for electrostatic deposition of drugs. Furthermore, all dilatation balloons are composed of polymeric materials, and as such are generally non-conductive. These polymers also cannot be grounded or biased to allow electrostatic deposition.
The present invention provides for methods of electrostatic coating of polymeric stents, stents that include a polymeric coating, or dilatation balloons of insufficient conductivity to be able to efficiently deposit a drug or other material.